Lung Cancer: GEB has been a pioneer in studies aimed at identifying a genetic component to common cancers using epidemiological study designs and we currently have a large lung cancer case-control study (see below- EAGLE, Environment and Genetics in Lung Cancer Etiology) with a major behavior and tissue component. Early work emphasized polymorphic genes (e.g., CYP2D6, GSTM1) that activate or detoxify carcinogens and thereby alter an individual's susceptibility to cancer when exposed to a specific agent however emphasis has now shifted to anonymous searches for candidate genes using high technology approaches. Lung cancer is a logical focus for these studies, because the environmental agent is well characterized (i.e., tobacco smoking), although only a minority of heavy smokers develop the disease. Furthermore, somatic gene mutations are well documented in lung tumors and relatives of people who develop the cancer are also at increased risk. To better understand the genetic component to smoking-related cancer we have conducted case-control studies of lung cancer with extensive biospecimen collection;studied determinants of the cancer in nonsmokers;studied cancer in different geographic, occupational, and ethnic groups;and examined tumor mutations in consecutive surgical cases. We are currently involved in studies to evaluate whether genes contribute to precursor conditions (i.e. emphysema) or to the key exposure (i.e. smoking). Families with lung and other smoking-related cancers have been studied, although suitable large, multi generation families are challenging to accrue because of the death toll for smoking-related diseases. Integrated Studies: In our single largest study, EAGLE involving over 2000 newly diagnosed lung cancer cases and 2000 population-based controls, we are investigating the genetic determinants of lung cancer and smoking in a multi-hospital, population-based case-control study of lung cancer with sufficient power to detect gene-environment interactions, biospecimen collection to allow interdisciplinary study of biomarkers from normal and neoplastic tissue, tissue collection from lung cancer surgical cases, and the planned study of genetic determinants of smoking in controls. Working closely with a team from caBIG, we have prepared a database structure to accomodate analysis of epidemiological data together anticipated high dimensional data from genomics, proteomics, expression and other work. We also participate in NCl's Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Study, a cohort study of 70,000 individuals in which large numbers of lung cancer cases will be identified over the next few years. Currently studies of the genetic determinants of emphysema and the genetic determinants of smoking are planned. Studies have been initiated involving possible infections agents (Chlamydia pneumoniae and H pylori), functional DNA repair, and the role of tobacco-related carcinogens (NNAL) in lung cancer. A Grant from GEI (Gene-Environment Initiative) was used t oconduct a GWAS on lung cancer and the smoking phenotype on over 5500 subjects from EAGLE and PLCO. Tobacco and Obesity: In the past we investigated the hypothesis of a genetic component to smoking and obesity using candidate gene approaches, e.g. publishing results immplicating polymorphisms affecting dopamine regulation and receptor stimulation as candidates for influencing genetic susceptibility to cigarette smoking as well as having a role in energy balance. Preliminary findings suggest that the dopamine transporter gene (DATI/ SLC6A3), which governs the reuptake of dopamine from the neuronal synapse, and the D2 dopamine receptor gene (DRD2), which is a postsynaptic receptor, may interact to influence smoking behavior. This finding suggests that smoking may be influenced by an interplay among multiple genes affecting dopaminergic reuptake and receptor stimulation. Understanding the mechanisms of dopaminergic genes in smoking may facilitate development of improved strategies to prevent smoking and help smokers quit the habit. Other pharmacogenetic hypotheses We used the Collaborative Perinatal Project to investigate the influence of genetic differences in phenytoin disposition in mothers on the presence of craniofacial abnormalities in the child. We identified 174 pregnacies in 155 women who used phenytoin throughout their pregnancy and identified 19 children with craniofacial abnormalities. Maternal EPHX genotype showed a significant protective association with craniofacial abnormalities in the child while CYP2C9 genotype was unrelated to fetal endpoints.